Raltegravir Salts And Crystalline Forms Thereof

ABSTRACT

The present invention includes new salts of Raltegravir and crystalline forms thereof, pharmaceutical compositions containing the salts or crystalline forms, methods of using the salts or crystalline forms or the compositions to treat HIV infection or to prepare medicament for treating HIV infection, and a process for preparing Raltegravir potassium.

This application is a continuation of U.S. application Ser. No.13/708,141, filed Dec. 7, 2012, which is a continuation of U.S.application Ser. No. 13/637,497, filed Sep. 26, 2012, which is theNational Stage Entry of International Application No. PCT/US2011/030892,filed Apr. 1, 2011, which claims the priority of U.S. Provisional PatentApplication Nos. 61/320,062 filed Apr. 1, 2010; 61/326,922 filed Apr.22, 2010; 61/329,284 filed Apr. 29, 2010; 61/353,398 filed Jun. 10,2010; 61/392,759 filed Oct. 13, 2010; 61/392,770 filed Oct. 13, 2010;and 61/417,632 filed Nov. 29, 2010, the disclosures of whichapplications are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention encompasses Raltegravir salts and their solidstate forms, as well as crystalline forms of Raltegravir potassium andsodium salts and of Raltegravir free hydroxy.

BACKGROUND OF THE INVENTION

Raltegravir, also referred to as Raltegravir free hydroxy,N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide,having the following formula;

is an antiretroviral drug used to treat HIV infection. Raltegravirtargets integrase, an HIV enzyme that integrates the viral geneticmaterial into human chromosomes, a critical step in the pathogenesis ofHIV. Raltegravir potassium salt is marketed under the trade nameISENTRESS™ by Merck & Co.

Raltegravir and its preparation are described in U.S. Pat. No.7,169,780. US Publication No. US 2006/0122205, WO 2010/140156 and WO2011/024192 describe potassium salt of Raltegravir including amorphousand crystalline forms I, II, III and H1 as well as amorphous andcrystalline forms of Raltegravir free-hydroxy.

The present invention relates to salts of Raltegravir, as well as solidstate forms of Raltegravir and Raltegravir salts. These properties canbe influenced by controlling the conditions under which Raltegravirpotassium, Raltegravir sodium, Raltegravir calcium, Raltegravirtert-butyl amine, Raltegravir lithium, Raltegravir diethylamine,Raltegravir diisopropylamine, Raltegravir meglumine and Raltegravir freehydroxy, are obtained in solid form.

Polymorphism, the occurrence of different crystal forms, is a propertyof some molecules and molecular complexes. A single molecule may giverise to a variety of polymorphs having distinct crystal structures andphysical properties like melting point, thermal behaviors (e.g. measuredby thermogravimetric analysis—“TGA”, or differential scanningcalorimetry—“DSC”), X-ray diffraction pattern, infrared absorptionfingerprint, and solid state NMR spectrum. One or more of thesetechniques may be used to distinguish different polymorphic forms of acompound.

Discovering new salts and new polymorphic forms and solvates of apharmaceutical product can provide materials having desirable processingproperties, such as ease of handling, ease of processing, storagestability, ease of purification or as desirable intermediate crystalforms that facilitate conversion to other polymorphic forms. Newpolymorphic forms and solvates of a pharmaceutically useful compound orsalts thereof can also provide an opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has available for formulationoptimization, for example by providing a product with differentproperties, e.g., better processing or handling characteristics,improved dissolution profile, or improved shelf-life. For at least thesereasons, there is a need for additional salts and solid state forms ofRaltegravir potassium, sodium, calcium, tert-butyl amine, meglumine,lithium, diethylamine and diisopropylamine salts and of Raltegravirfree-hydroxy.

SUMMARY OF THE INVENTION

The present invention provides salts of Raltegravir and crystallineforms thereof and of Raltegravir free hydroxy, processes for preparingthem, and pharmaceutical composition containing them.

The present invention also encompasses the use of any one of theRaltegravir salts, Raltegravir free-hydroxy and crystalline formsthereof of the present invention for the preparation of Raltegravirpotassium or formulation thereof, for use as medicaments, particularlyfor the treatment of HIV infection.

The present invention also provides a process for preparing Raltegravirpotassium, by preparing any one of the Raltegravir salts and crystallineforms thereof or of Raltegravir free-hydroxy, and converting it toRaltegravir potassium.

The present invention further provides a pharmaceutical compositioncomprising any one of the Raltegravir salts, Raltegravir free-hydroxyand crystalline forms thereof of the present invention and at least onepharmaceutically acceptable excipient, for use as medicaments,particularly for the treatment of HIV infection.

The present invention also provides a method of treating HIV infection,comprising administering a therapeutically effective amount of at leastone of the Raltegravir salts, Raltegravir free-hydroxy and crystallineforms thereof of the present invention, or at least one of the abovepharmaceutical compositions to a person suffering from an HIV

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffractogram of Raltegravir potassium FormIV.

FIG. 2 shows an X-ray powder diffractogram of Raltegravir potassium FormV.

FIG. 3 shows an X-ray powder diffractogram of Raltegravir potassium FormVI.

FIG. 4 shows an X-ray powder diffractogram of Raltegravir potassium FormVII.

FIG. 5 shows an X-ray powder diffractogram of Raltegravir potassium FormVIII.

FIG. 6 shows an X-ray powder diffractogram of Raltegravir potassium FormIXa.

FIG. 7 shows an X-ray powder diffractogram of Raltegravir potassium FormIXb.

FIG. 8 shows an X-ray powder diffractogram of Raltegravir potassium FormX, with the values in the horizontal axis expressed in degrees 2θ.

FIG. 9 shows an X-ray powder diffractogram of Raltegravir potassium FormXI.

FIG. 10 shows an X-ray powder diffractogram of Raltegravir potassiumForm XII.

FIG. 11 shows an X-ray powder diffractogram of Raltegravir potassiumForm XIII.

FIG. 12 shows an X-ray powder diffractogram of Raltegravir sodium FormS1.

FIG. 13 shows an X-ray powder diffractogram of Raltegravir sodium FormS2.

FIG. 14 shows an X-ray powder diffractogram of Raltegravir sodium FormS3.

FIG. 15 shows an X-ray powder diffractogram of Raltegravir lithium salt.

FIG. 16 shows an X-ray powder diffractogram of Raltegravir calcium salt

FIG. 17 shows an X-ray powder diffractogram of Raltegravir tert-butylamine salt.

FIG. 18 shows an X-ray powder diffractogram of Raltegravir diethylaminesalt

FIG. 19 shows an X-ray powder diffractogram of Raltegravirdiisopropylamine salt

FIG. 20 shows an X-ray powder diffractogram of Raltegravir potassiumForm XIV.

FIG. 21 shows an X-ray powder diffractogram of Raltegravir potassiumForm XV

FIG. 22 shows an X-ray powder diffractogram of Raltegravir potassiumForm XVI.

FIG. 23 shows an X-ray powder diffractogram of Raltegravir free hydroxyForm A1.

FIG. 24 shows an X-ray powder diffractogram of Raltegravir free hydroxyForm A2.

FIG. 25 shows an X-ray powder diffractogram of Raltegravir free hydroxyForm A3.

FIG. 26 shows an X-ray powder diffractogram of Raltegravir tert-butylamine salt.

FIG. 27 shows a DSC thermogram for Raltegravir potassium form IV.

FIG. 28 shows a TGA thermogram of Raltegravir potassium form IV.

FIG. 29 shows a DSC thermogram for Raltegravir potassium form V.

FIG. 30 shows a TGA thermogram of Raltegravir potassium form V.

FIG. 31 shows a solid-state ¹³C NMR spectrum of Raltegravir potassiumform V.

FIG. 32 shows an FT Raman spectrum of Raltegravir potassium form V.

FIG. 33 shows a solid-state ¹³C NMR spectrum of Raltegravir sodium formS2.

FIG. 34 shows a solid-state ¹³C NMR spectrum of crystalline Raltegravirtert-butyl amine.

FIG. 35 shows an FT Raman spectrum of Raltegravir meglumine salt.

FIG. 36 shows an X-ray powder diffractogram of amorphous Raltegravirmeglumine salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses the following new salts and solidstate forms of Raltegravir: Raltegravir calcium salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidecalcium salt); Raltegravir tert-butyl amine salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidetert-butyl amine salt); Raltegravir meglumine salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidemeglumine salt); Raltegravir lithium salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidelithium salt); Raltegravir diethylamine salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidediethylamine salt); and Raltegravir diisopropylamine salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidediisopropylamine salt).

The present invention also encompasses crystalline forms of Raltegravirpotassium salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidepotassium salt); Raltegravir sodium salt(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamidesodium salt); and Raltegravir free-hydroxy(N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide).

In some embodiments, salts and solid state forms of Raltegravir of theinvention are substantially free of any other salts, polymorphic forms,or of specified polymorphic forms of Raltegravir, respectively. In anyembodiment of the present invention, by “substantially free” is meantthat the forms of the present invention contain 20% (w/w) or less, 10%(w/w) or less, 5% (w/w) or less, 2% (w/w) or less, particularly 1% (w/w)or less, more particularly 0.5% (w/w) or less, and most particularly0.2% (w/w) or less of any other salts, polymorphs or of a specifiedpolymorph of Raltegravir. In other embodiments, the salts and polymorphsof Raltegravir potassium, sodium, calcium, tert-butyl amine, meglumine,lithium, diethylamine or diisopropylamine salts and of Raltegravirfree-hydroxy of the invention contain from 1% to 20% (w/w), from 5% to20% (w/w), or from 5% to 10% (w/w) of any other salts, polymorphs or ofa specified polymorph of Raltegravir.

The present invention addresses a need in the art by providing newcrystalline forms of Raltegravir potassium, Raltegravir sodium,Raltegravir free-hydroxy and other Raltegravir salts (particularly,lithium, calcium, tert-butylamine, meglumine, diethylamine ordiisopropylamine salts) that have advantageous properties selected fromat least one of: chemical purity, flowability, solubility, dissolutionrate, morphology or crystal habit, stability-such as thermal andmechanical stability to polymorphic conversion, stability to dehydrationand/or storage stability, low content of residual solvent, a lowerdegree of hygroscopicity, flowability, and advantageous processing andhandling characteristics such as compressibility, and bulk density.

A crystal form may be referred to herein as being characterized bygraphical data “as depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. Theskilled person will understand that such graphical representations ofdata may be subject to small variations, e.g., in peak relativeintensities and peak positions due to factors such as variations ininstrument response and variations in sample concentration and purity,which are well known to the skilled person. Nonetheless, the skilledperson would readily be capable of comparing the graphical data in theFigures herein with graphical data generated for an unknown crystal formand confirm whether the two sets of graphical data are characterizingthe same crystal form or two different crystal forms. A crystal form ofa Raltegravir salt referred to herein as being characterized bygraphical data “as depicted in” a Figure will thus be understood toinclude any crystal forms of the Raltegravir salt characterized with thegraphical data having such small variations, as are well known to theskilled person, in comparison with the Figure.

As used herein, the term “monohydrate” refers to hydrate containg waterin crystal lattice, in equimolar amount compared to the compound. Inparticularly, the compound is Raltegravir potassium.

As used herein, the term “solvate” refers to a crystal latticecontaining solvent. Particularry, the crystal lattice is of Raltegravirpotassium and the solvent is NMP.

As used herein, the term “isolated” in reference to any of Raltegravirsalts or polymorphs thereof of the present invention corresponds toRaltegravir salt or polymorph thereof that is physically separated fromthe reaction mixture, where it is formed.

As used herein, unless stated otherwise, the XRPD measurements are takenusing copper Ku radiation wavelength 1.54 Å.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature, often abbreviated “RT.”This means that the temperature of the thing is close to, or the sameas, that of the space, e.g., the room or fume hood, in which the thingis located. Typically, room temperature is from about 20° C. to about30° C., or about 22° C. to about 27° C., or about 25° C.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, typically about 16 hours.

As used herein, the term “reduced pressure” refers to a pressure ofabout 10 mbar to about 50 mbar.

As used herein, the terms “vol.” or “volume” can be used to refer to mlper gram of the corresponding raltegravir. For example, a statement that0.5 g of Raltegravir is dissolved in ten volumes of a Solvent X would beunderstood to mean that the 0.5 g of Raltegravir was dissolved in 5 mlof Solvent X.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form IV. Form IV can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 6.5,7.5, 8.1, 18.4 and 23.2 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 1;and combinations thereof. Crystalline Form IV of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 13.0, 17.5, 24.2 and 25.5 degrees twotheta±0.2 degrees two theta; a DSC thermogram as depicted in FIG. 27; aTGA thermogram as depicted in FIG. 28; and combinations thereof.

Typically, Raltegravir potassium Form IV can be an N-methyl-pyrrolidone(“NMP”) solvate.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form V. Form V can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 8.0,11.9, 18.2 and 26.6 degrees two theta±0.2 degrees two theta; an X-raypowder diffraction pattern substantially as depicted in FIG. 2; asolid-state ¹³C NMR spectrum with signals at 121.9, 144.0, 149.3 and170.3±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shiftsdifferences between the signal exhibiting the lowest chemical shift andanother in the chemical shift range of 100 to 180 ppm of 111.9, 134.0,139.3 and 160.3±0.1 ppm; a solid-state ¹³C NMR spectrum substantially asdepicted in FIG. 31; and combinations thereof. Crystalline Form V ofRaltegravir potassium may be further characterized by the X-ray powderdiffraction pattern having additional peaks at 14.9, 19.8, 24.9, 27.7and 28.9 degrees two theta±0.2 degrees two theta; a DSC thermogram asdepicted in FIG. 29; a TGA thermogram as depicted in FIG. 30; an FTRaman spectrum as depicted in FIG. 32; and combinations thereof.

Typically, Raltegravir potassium Form V can be a monohydrate, forexample, it can contain from about 3.4% to about 3.8% of water,specifically, about 3.6% of water by weight.

As discussed above, Raltegravir potassium Form V has advantageousproperties. In particular, the crystalline Raltegravir potassium Form Vof the present invention has a significantly higher dissolution ratecompared with the Raltegravir potassium Form I disclosed in U.S. Pat.No. 7,754,731, which lead to favourable pharmacokinetics, e.g. increasedbioavailability of Raltegravir.

Raltegravir potassium Form V of the present invention may be prepared bya process comprising: combining Raltegravir free-hydroxy withtetrahydrofuran (“THF”) to obtain a reaction mixture; and adding anaqueous solution of KOH. Typically, the Raltegravir free hydroxy isRaltegravir free hydroxy Form A1. The addition of the aqueous solutionof KOH may be followed by a cooling step. The cooling may be done to atemperature such as about −10° C. to about 5° C., or about 0° C. Thecooling may be followed by seeding with Raltegravir potassium Form V.Following the cooling, the reaction mixture may be maintained, typicallywhile stirring. The maintaining may be done for a time period such asabout 2.5 hours to about 48 hours, for example, for about 2.5 hours. Theobtained Raltegravir potassium may further be isolated. The isolationmay be done by filtering and washing with a suitable solvent, preferablya water miscible solvent such as THF. Typically, the filtering is doneat room temperature. Optionally, the isolated precipitate is furtherdried.

The present invention further encompasses a crystalline form ofRaltegravir potassium, designated as Form VI. Form VI can becharacterized by data selected from: an X-ray powder diffraction patternhaving peaks at 5.7, 12.7, 17.1, 19.7 and 25.4 degrees two theta±0.2degrees two theta; an X-ray powder diffraction pattern substantially asdepicted in FIG. 3; and combinations thereof. Crystalline Form VI ofRaltegravir potassium may be further characterized by the X-ray powderdiffraction pattern having additional peaks at 11.4, 15.8 and 20.3degrees two theta±0.2 degrees two theta.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form VII. Form VII can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 7.4,11.1, 16.0 and 25.8 degrees two theta±0.2 degrees two theta; an X-raypowder diffraction pattern substantially as depicted in FIG. 4; andcombinations thereof. Crystalline Form VII of Raltegravir potassium maybe further characterized by the X-ray powder diffraction pattern havingadditional peaks at 22.4, 25.2, 26.7 and 28.7 degrees two theta±0.2degrees two theta.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form VIII. Form VIII can be characterized bydata selected from: an X-ray powder diffraction pattern having peaks at5.4, 7.4, 13.1, 13.4, 20.6, 22.3, 24.6 and 26.4 degrees two theta±0.2degrees two theta; an X-ray powder diffraction pattern substantially asdepicted in FIG. 5; and combinations thereof. Crystalline Form VIII ofRaltegravir potassium may be further characterized by the X-ray powderdiffraction pattern having additional peaks at 14.6, 20.1, 23.0, 24.1,27.9, 28.9 and 29.5 degrees two theta±0.2 degrees two theta.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form IXa. Form IXa can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 5.3,7.2, 8.2, 10.6 and 13.7 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 6;and combinations thereof. Crystalline Form IXa of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 16.0, 17.2, 18.6, 21.4 and 24.3 degrees twotheta±0.2 degrees two theta.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form IXb. Form IXb can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 5.3,7.8, 8.2, 10.6, 12.2 and 13.7 degrees two theta±0.2 degrees two theta;an X-ray powder diffraction pattern substantially as depicted in FIG. 7;and combinations thereof. Crystalline Form IXb of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 18.9, 19.8, 20.1, 21.5, 22.2 and 24.3 degreestwo theta±0.2 degrees two theta.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form X. Form X can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 5.7,8.3, 15.4, 19.1, 19.8 and 20.3 degrees two theta±0.2 degrees two theta;an X-ray powder diffraction pattern substantially as depicted in FIG. 8;and combinations thereof. Crystalline Form X of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 22.5, 24.5, 25.4 and 26.8 degrees twotheta±0.2 degrees two theta.

The present invention encompasses a crystalline form of Raltegravirpotassium, designated as Form XI. Form XI can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 7.9,14.5, 15.8, 17.3, 21.1 and 23.0 degrees two theta±0.2 degrees two theta;an X-ray powder diffraction pattern substantially as depicted in FIG. 9;and combinations thereof.

The present invention comprises a crystalline form of Raltegravirpotassium, designated as Form XII. Form XII can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 5.2;8.3; 15.5; 19.1; and 28.5 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 10;and combinations thereof. Crystalline Form XII of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 7.0; 7.5; 11.8; 12.3; 14.7; and 18.1 degreestwo theta±0.2 degrees two theta.

The present invention comprises a crystalline form of Raltegravirpotassium, designated as Form XIII. Form XIII can be characterized bydata selected from: an X-ray powder diffraction pattern having peaks at5.1; 7.2; 7.7; 7.9; 11.9; and 24.3 degrees two theta±0.2 degrees twotheta; an X-ray powder diffraction pattern substantially as depicted inFIG. 11; and combinations thereof.

The present invention comprises a crystalline form of Raltegravirpotassium, designated as Form XIV. Form XIV can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 4.9,7.7, 19.4, 24.1 and 25.9 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 20;and combinations thereof. Crystalline Form XIV of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 13.4, 13.8, 21.3, 24.5 and 30.8 degrees twotheta±0.2 degrees two theta.

The present invention comprises a crystalline form of Raltegravirpotassium, designated as Form XV. Form XV can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 5.2,11.5, 15.6 and 23.1 degrees two theta±0.2 degrees two theta; an X-raypowder diffraction pattern substantially as depicted in FIG. 21; andcombinations thereof. Crystalline Form XV of Raltegravir potassium maybe further characterized by the X-ray powder diffraction pattern havingadditional peaks at 11.9, 12.9, 18.6 and 25.5 degrees two theta±0.2degrees two theta.

The present invention comprises a crystalline form of Raltegravirpotassium, designated as Form XVI. Form XVI can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 4.6,9.3, 13.9, 18.2 and 18.6 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 22;and combinations thereof. Crystalline Form XVI of Raltegravir potassiummay be further characterized by the X-ray powder diffraction patternhaving additional peaks at 13.4, 15.0, 22.1, and 23.6 degrees twotheta±0.2 degrees two theta.

The present invention encompasses isolated Raltegravir sodium salt.Typically, the Raltegravir sodium salt can be in a crystalline form.

The present invention encompasses a crystalline form of Raltegravirsodium, designated as Form S1. Form S1 can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 7.9,11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 12;and combinations thereof. Crystalline Form S of Raltegravir sodium maybe further characterized by the X-ray powder diffraction pattern havingadditional peaks at 14.0, 15.0, 23.9 and 27.8 degrees two theta±0.2degrees two theta.

The present invention encompasses a crystalline form of Raltegravirsodium, designated as Form S2. Form S2 can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 7.8,11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta; an X-raypowder diffraction pattern substantially as depicted in FIG. 13; asolid-state ¹³C NMR spectrum with signals at 134.3, 146.1, 149.0, 153.9and 170.5±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shiftsdifferences between the signal exhibiting the lowest chemical shift andanother in the chemical shift range of 100 to 180 ppm of 124.3, 136.1,139.0, 143.9 and 160.5±0.1 ppm; a solid-state ¹³C NMR spectrumsubstantially as depicted in FIG. 33; and combinations thereof.Crystalline Form S2 of Raltegravir sodium may be further characterizedby the X-ray powder diffraction pattern having additional peaks at 14.6,17.2, 23.6, 28.1 and 29.1 degrees two theta±0.2 degrees two theta.

The present invention encompasses a crystalline form of Raltegravirsodium, designated as Form S3. Form S3 can be characterized by dataselected from: an X-ray powder diffraction pattern having peaks at 8.1,13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta; anX-ray powder diffraction pattern substantially as depicted in FIG. 14;and combinations thereof. Crystalline Form S3 of Raltegravir sodium maybe further characterized by the X-ray powder diffraction pattern havingadditional peaks at 20.3, 23.1, 27.4, 30.2 and 32.5 degrees twotheta±0.2 degrees two theta.

As discussed above the crystalline forms of Raltegravir sodium of thepresent invention (namely, Form S1, Form S2 and Form S3) haveadvantageous properties. In particular, the crystalline forms ofRaltegravir sodium of the present invention have a significantly higherdissolution rate compared with the Raltegravir potassium form Idisclosed in U.S. Pat. No. 7,754,731, which lead to favourablepharmacokinetics, e.g. increased bioavailability of Raltegravir.

The present invention further comprises novel salts of Raltegravir, inparticular: lithium, calcium, tert-butylamine, meglumine, diethylamine,diisopropylamine salts. The above salts can be isolated. Preferably, theabove salts are in crystalline form.

In one embodiment, the present invention comprises a Raltegravir lithiumsalt.

In one embodiment, the present invention comprises a crystalline form ofthe lithium salt characterized by data selected from: an X-ray powderdiffraction pattern with peaks at 10.4; 11.9; 15.6; 17.2; 20.3 degreestwo theta±0.2 degrees two theta; an X-ray powder diffraction patternsubstantially as depicted in FIG. 15, and combinations thereof. Theabove crystalline form of Raltegravir lithium salt can be furthercharacterized by X-ray powder diffraction pattern having additionalpeaks at 8.1, 14.4, 21.3, 25.3, and 30.1 degrees two theta±0.2 degreestwo theta.

In one embodiment, the present invention comprises a crystalline form ofRaltegravir calcium salt characterized by data selected from: an X-raypowder diffraction pattern with peaks at 6.5; 9.9; 18.0; 19.0 and 21.1degrees two theta±0.2 degrees two theta; an X-ray powder diffractionpattern substantially as depicted in FIG. 16, and combinations thereof.

In one embodiment, the present invention comprises a crystalline form ofRaltegravir tert-butyl amine salt characterized by data selected from:an X-ray powder diffraction pattern with peaks at 12.4; 16.7; 17.9; 18.6and 20.9 degrees two theta±0.2 degrees two theta; an X-ray powderdiffraction pattern with peaks at 4.2; 6.6; 8.4; 16.9 and 21.1 degreestwo theta±0.2 degrees two theta; an X-ray powder diffraction patternsubstantially as depicted in FIG. 17 or 26; a solid-state ¹³C NMRspectrum with signals at 121.7, 130.2, 141.6, 152.0±0.2 ppm; asolid-state ¹³C NMR spectrum having chemical shifts differences betweenthe signal exhibiting the lowest chemical shift and another in thechemical shift range of 100 to 180 ppm of 110.4, 118.9, 130.3 and140.7±0.1 ppm; a solid-state ¹³C NMR spectrum substantially as depictedin FIG. 34; and combinations thereof. The above crystalline form ofRaltegravir tert-butyl amine salt can be further characterized by X-raypowder diffraction pattern having additional peaks at 9.0; 13.6; 15.0;and 22.6 degrees two theta±0.2 degrees two theta. Alternatively, thecrystalline form of Raltegravir tert-butyl amine salt as defined in anyof the above data may be further characterized by XRPD pattern havingadditional peaks at: 9.2; 10.2; 12.6; 13.8; 15.2 and 18.0 degrees twotheta±0.2 degrees two theta.

In one embodiment, the present invention comprises a crystalline form ofRaltegravir diethylamine salt characterized by data selected from: anX-ray powder diffraction pattern with peaks at 7.0; 12.6; 13.9; 17.8;26.9 degrees two theta±0.2 degrees two theta; an X-ray powderdiffraction pattern substantially as depicted in FIG. 18, andcombinations thereof. The above crystalline form of Raltegravir can befurther characterized by X-ray powder diffraction having additionalpeaks at 10.8; 19.8; 21.6; and 23.2 degrees two theta±0.2 degrees twotheta

In one embodiment, the present invention comprises a crystalline form ofRaltegravir diisopropylamine salt characterized by data selected from:an X-ray powder diffraction pattern with peaks at 12.6; 16.9; 17.6;17.9; and 21.2 degrees two theta±0.2 degrees two theta; an X-ray powderdiffraction pattern substantially as depicted in FIG. 19, andcombinations thereof. The above crystalline form of Raltegravir can befurther characterized by X-ray powder diffraction pattern havingadditional peaks at 6.2; 8.8; 19.3; 23.0; and 26.8 degrees two theta±0.2degrees two theta.

In one embodiment, the present invention comprises Raltegravir megluminesalt. The Raltegravir meglumine salt can be characterized by dataselected from: FT Raman spectrum with peaks at: 1426.9, 850.7, 3075.3,2945.6, 1575.7, 1426.9, 1339.1, 1052.9, 850.7, 827.8 cm⁻¹±2 cm⁻¹; FTRaman spectrum substantially as depicted in FIG. 35; and combinationsthereof.

The Raltegravir meglumine may be in amorphous form. The amorphous formof Raltegravir meglumine salt can be characterized by X-ray powderdiffraction pattern substantially as depicted in FIG. 36.

As discussed above, Raltegravir meglumine salt has advantageousproperties. In particular, the Raltegravir meglumine of the presentinvention has a significantly higher dissolution rate compared with theRaltegravir potassium form I disclosed in U.S. Pat. No. 7,754,731, whichlead to favourable pharmacokinetics, e.g. increased bioavailability ofRaltegravir.

The present invention also describes crystalline forms of Raltegravirfree hydroxy.

In one embodiment, the present invention comprises a crystalline form ofRaltegravir free hydroxy, designated as Form A1. Form A1 can becharacterized by data selected from: an X-ray powder diffraction patternhaving peaks at 6.4, 8.3, 10.9, 12.8 and 15.6 degrees two theta±0.2degrees two theta; an X-ray powder diffraction pattern as depicted inFIG. 23; and combinations thereof. Crystalline Form A1 of Raltegravirfree hydroxy may be further characterized by the X-ray powderdiffraction pattern having additional peaks at 11.9, 13.8, 16.3, 21.7and 23.8 degrees two theta±0.2 degrees two theta.

In another embodiment, the present invention comprises a crystallineform of Raltegravir free hydroxy, designated as Form A2. Form A2 can becharacterized by data selected from: an X-ray powder diffraction patternhaving peaks at 8.1, 13.6, 15.1, 16.1, 22.6 and 23.1 degrees twotheta±0.2 degrees two theta; an X-ray powder diffraction pattern asdepicted in FIG. 24; and combinations thereof. Crystalline Form A2 ofRaltegravir free hydroxy may be further characterized by the X-raypowder diffraction pattern having additional peaks at 20.3, 25.5, 27.4,30.2 and 32.5 degrees two theta±0.2 degrees two theta.

In another embodiment, the present invention comprises a crystallineform of Raltegravir free hydroxy, designated as Form A3. Form A3 can becharacterized by data selected from: an X-ray powder diffraction patternhaving peaks at 7.8, 11.8, 15.5, 16.3, 23.3 and 28.5 degrees twotheta±0.2 degrees two theta; an X-ray powder diffraction patternsubstantially as depicted in FIG. 25; and combinations thereof.Crystalline Form A3 of Raltegravir free hydroxy may be furthercharacterized by the X-ray powder diffraction pattern having additionalpeaks at 13.5, 18.4, 22.0, 25.1, and 26.7 degrees two theta±0.2 degreestwo theta.

The above crystalline Forms of Raltegravir free hydroxy can be used toprepare Raltegravir salts such as Raltegravir potassium, for example, byreacting Raltegravir free hydroxy with a base such as potassium base, asdescribed in U.S. Patent Application Publication No. US 2006/0122205,Example 1, step 9, or formulation thereof.

The above described salts and solid state forms of Raltegravir can beused to prepare Raltegravir potassium salt and pharmaceuticalformulation thereof.

The present invention encompasses a process for preparing Raltegravirpotassium comprising preparing any one of the above salts and solidstate forms of Raltegravir by the processes of the present invention andconverting it to Raltegravir potassium. The conversion may be done forexample, by acidifying the Raltegravir salt to obtain Raltegravir freehydroxy and further reacting the formed Raltegravir free-hydroxy with apotassium base.

The present invention further encompasses 1) a pharmaceuticalcomposition comprising any one or combination of the Raltegravir saltsor of Raltegravir free-hydroxy and crystalline forms thereof, asdescribed above, and at least one pharmaceutically acceptable excipient;and 2) the use of any one or combination of the above-describedRaltegravir salts or of Raltegravir free-hydroxy and crystalline formsthereof, in the manufacture of a pharmaceutical composition, and 3) amethod of treating a person suffering from HIV infection, comprisingadministration of an effective amount of a pharmaceutical compositioncomprising any one or more of the forms of Raltegravir salts or ofRaltegravir free hydroxy described herein.

The pharmaceutical composition can be useful for the treatment orprophylaxis of HIV infection. The present invention also providesRaltegravir slats or Raltegravir free-hydroxy and crystalline formsthereof as described above for use as a medicament, preferably for thetreatment or prophylaxis of HIV infection.

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to limit its scope in any way.

X-Ray Powder Diffraction (“XRPD”) Method:

The X-ray powder diffraction analyses of the crystalline forms of theRaltegravir salts and of the Raltegravir free-hydroxy were performed onone of two different X-ray diffractometers, giving the same results. Oneinstrument was a Thermo ARL, Scintag X-ray powder diffractometer modelX'TRA. Analyses on the Scintag diffractometer were done with a Cu-tubesolid-state detector, round standard aluminum sample holder with roundzero background quartz plate. Copper Kα₁ radiation (λ=1.54 Å) was used.The scanning parameters were: range: 2-40 degrees two-theta; scan mode:continuous scan; step size: 0.05 deg.; and scan rate: 3 deg/min. Theother instrument was a Philips X'Pert PRO powder diffractometer. Whenusing this instrument, sample was applied directly on silicon PW1817/32“zero background” holder. X-Ray tube was PW3373/00; Cu anode LFF andX-ray radiation λ(CuKα₁)=1.54 Å. The scanning parameters were: range:2-40 degrees two-theta; scan mode: continuous scan; step size: 0.0167deg.; and scan rate: 0.05 deg/sec.

The peak positions were determined by using silicon powder as internalstandard in an admixture with the sample measured. The position of thesilicon (111) peak was corrected to be 28.45 degrees two theta. Thepositions of the peaks were corrected respectively, but no correctionswere performed on the diffractograms in the figures provided herein).

Differential Scanning Calorimetry (“DSC”) method:

Instrument DSC Q1000 V9.8 Build 296 Module: DSC Standard Cell RC

Pan: Aluminum standardGas: Nitrogen 50.0 ml/mlRamp: 10° C./min from 25 to 300° C.

Thermogravimetric analysis (“TGA”) method:

Instrument AutoTGA 2950HR V5.4 A Module TGA 1000° C.

Sample size about 20 mg

Pan: Platinum

Gas 1: Nitrogen 60 ml/min

RAMAN methods:

RAMAN method for measuring Raltegravir potassium form V:Powder samples were filled into 5 mm NMR tube and Raman spectra wererecorded on Nicolet 6700 FT-IR spectrometer with NXR FT-Raman module,equipped with 1064 nmNd:YVO₄ excitation laser, CaF₂ beamsplitter and Ge detector.Instrument parameters:Spectral range: 4000-155 cm⁻¹Resolution: 4.0 cm⁻¹Number of scans: 128Laser power: 1.5 W

RAMAN method for measuring Raltegravir meglumine salt:

Instrument: MultiRam, Bruker, T. No. IRFS27, equipped with HPGe NIRdetector,Laser: 9395.2 cm⁻¹Laser power: 150 mWResolution: 4 cm⁻¹Number of scans: 20.

EXAMPLES Reference Examples

The starting Raltegravir free hydroxy and Raltegravir potassium can beprepared according to the methods described in US 2006/0122205,incorporated herein by reference.

The starting amorphous Raltegravir potassium can be prepared bydissolving Raltegravir potassium (45 g) in water (10-30 vol.) andpumping the resulting solution into spray dryer at room temperature. Theinlet temperature was set to 120-130° C., and the outlet temperature75-80° C. Alternatively, amorphous Raltegravir potassium was preparedaccording to the process described in example 15 below.

Example 1 Preparation of Raltegravir Potassium Form IV

A vial (20 ml) was charged with Raltegravir free hydroxy (500 mg)completely dissolved in N-methyl-pyrrolidone (NMP) (1.5 ml) at roomtemperature. A solution of 30% aqueous KOH (0.162 ml) was added. Themixture was stirred for 21 h at room temperature. Additional NMP (7.5ml) was added and the mixture was stirred for an additional 6.5 h atroom temperature. A solid precipitated and was filtered under reducedpressure to provide wet Raltegravir potassium crystalline Form IV. Thewet product was dried overnight in a vacuum oven at 40° C. to provideRaltegravir potassium crystalline Form IV.

Example 2 Preparation of Raltegravir Potassium Form V

A vial (20 ml) was charged with Raltegravir free hydroxy (500 mg) andcyclohexane (2.5 ml) at room temperature. A solution of 30% aqueous KOH(0.162 ml) was added. An additional amount of cyclohexane (5 ml) wasadded. The mixture was stirred for 25 h at room temperature. A gel solidprecipitated and was removed Form the mixture using a spatula and wasthen filtered under reduced pressure to produce wet Raltegravirpotassium crystalline Form V. The product was dried overnight in avacuum oven at 40° C. to provide raltegravir potassium crystalline FormV.

Example 3 Preparation of Raltegravir Potassium Form V

A vial (20 ml) was charged with Raltegravir potassium (300 mg)completely dissolved in distilled water (11 ml) at room temperature. Thesolution was concentrated using a rotary evaporator to provide wetRaltegravir potassium crystalline Form V.

Example 4 Preparation of Raltegravir Potassium Form V

A vial (20 ml) was charged with amorphous Raltegravir potassium (200 mg)and 2 drops of distilled water were added. The mixture was stirred on arotary evaporator without vacuum for 1 h at room temperature. Theproduct was dried overnight in a vacuum oven at 45° C. to obtainRaltegravir potassium crystalline Form V.

Example 5 Preparation of Raltegravir Potassium Form V

Amorphous Raltegravir potassium (1 g) in distilled water (1 mL) wasstirred on a rotary evaporator without vacuum for 80 minutes at roomtemperature. The obtained product was isolated by vacuum filtration andwashed with distilled water (0.75 ml). The product was dried overnightin a vacuum oven at 45° C. to obtain Raltegravir potassium crystallineForm V.

Example 6 Preparation of Raltegravir Potassium Form V

A vial (20 mL) charged with Raltegravir free Form A1 (0.5 g) and amixture of Heptane and water (9:1, 10 vol). KOH 30% (1 eq) was added atroom temperature. Seeds of Raltegravir potassium Form V were added. Thethus-formed sticky slurry was stirred for 4 hours and then filtered. Thethus obtained product was dried in a vacuum oven at 40° C. for overnightto obtain Raltegravir potassium crystalline Form V.

Example 7 Preparation of Raltegravir Potassium Form V

A 50 mL flask equipped with mechanical stirrer was charged with water (1vol), KOH 85% (1 eq) and Raltegravir free Form A1 (1 g). A clearsolution was obtained. Heptane (9 vol) was added at room temperature.Seeds of Raltegravir potassium Form V were added, thus forming a slurry.The slurry was stirred for 2.5 hours and then filtered; the product wasdried in a vacuum oven at 40° C. for overnight to obtain Raltegravirpotassium crystalline Form V.

Example 8 Preparation of Raltegravir Potassium Form V

A 50 mL flask equipped with mechanical stirrer was charged with water (1vol), KOH 85% (1 eq) and Raltegravir free Form A1 (1 g). A clearsolution was obtained. The solution was cooled in ice bath. Toluene (9vol) was added. Seeds of Raltegravir potassium Form V were added, thusforming a slurry. The slurry was stirred for 2.5 hours and then filteredthe thus obtained product was dried in a vacuum oven at 40° C. forovernight to obtain Raltegravir potassium crystalline Form V.

Example 9 Preparation of Raltegravir Potassium Form V

A 50 mL flask equipped with mechanical stirrer was charged with water (2vol), KOH 85% (1 eq) and RLT free Form A1 (1 g). A clear solution wasobtained. The solution was cooled in ice bath. Heptane (8 vol) wasadded; followed by addition of seeds of Raltegravir potassium Form V.The thus-formed sticky slurry was stirred for 2.5 hours and filtered.The thus obtained product was dried in a vacuum oven at 40° C. forovernight to obtain Raltegravir potassium crystalline Form V.

Example 10 Preparation of Raltegravir Potassium Form V

A 50 mL flask equipped with mechanical stirrer was charged with water (1vol), KOH 85% (1 eq) and Raltegravir free Form A1 (1 g). A clearsolution was obtained. The solution was cooled in ice bath. Heptane (9vol), and seeds of Raltegravir potassium Form V were added. The thusformed sticky slurry was stirred for 2.5 hours and filtered. The thusobtained product was dried in a vacuum oven at 40° C. for overnight toobtain Raltegravir potassium crystalline Form V.

Example 11 Preparation of Raltegravir Potassium Form VI

A vial (20 ml) was charged with Raltegravir free hydroxy (200 mg) slurryin EtOH:H₂O (1000:1, 0.2 ml) at room temperature. The slurry was heatedto 50° C. A solution of 45% aqueous KOH (0.044 ml) was added at 50° C.to the mixture. The resulting mixture was stirred for 5.5 h at 50° C. Tothis mixture was added distilled H₂O (1.5 ml) dropwise to produce acolorless solution. The solvent was then removed under reduced pressureto provide wet Raltegravir potassium crystalline Form VI. The productwas dried in a vacuum oven at 40° C. for 3.5 hours to provideRaltegravir potassium crystalline Form VI.

Example 12 Preparation of Raltegravir Potassium Form VII

A flask (100 ml) was charged with Raltegravir free hydroxy (500 mg)completely dissolved in 1,4-dioxane (35 ml) at room temperature. Asolution of 30% aqueous KOH (0.162 ml) was added. The resulting mixturewas stirred for 24 h at room temperature. A solid precipitated and wasfiltered under reduced pressure to provide wet Raltegravir potassiumcrystalline Form VII.

Example 13 Preparation of Raltegravir Potassium Form VII

A vial (20 ml) was charged with amorphous Raltegravir potassium (500 mg)and dichloromethane (2.5 mL). The mixture was stirred in a sonicator for50 minutes at room temperature. The product was filtered and then wasdried overnight in a vacuum oven at 45° C. to obtain Raltegravirpotassium crystalline Form VII.

Example 14 Preparation of Raltegravir Potassium Form VIII

A vial (20 ml) was charged with amorphous Raltegravir potassium (500 mg)and dry ethanol (2.5 ml) to form a slurry. The slurry was stirred for 24h at 60° C. Dry ethanol (2.5 ml) was added and the resulting mixture wasstirred for an additional 7.5 h at 60° C. The product was isolated byvacuum filtration and washed with dry ethanol (0.5 ml). The wetRaltegravir potassium was obtained as crystalline Form VIII.

Example 15 Preparation of Raltegravir Potassium Form IXa

A vial (20 ml) was charged with amorphous Raltegravir potassium (500 mg)and cyclohexane (2.5 mL) to form a mixture. The mixture was stirred for24 hours at room temperature, and then heated to 60° C. and stirred at60° C. for additional 24 hours. The cyclohexane evaporated overnight andtherefore an additional amount of cyclohexane (2 mL) was added. Theobtained product was isolated by vacuum filtration and then was driedovernight in a vacuum oven at 45° C. to obtain amorphous Raltegravirpotassium. The amorphous Raltegravir potassium was heated to 250° C. ata heating rate of 10° C./min in an aluminum (standard DSC) crucible toobtain Raltegravir potassium Form IXa.

Example 16 Preparation of Raltegravir Potassium Form IXb

A vial (20 ml) was charged with amorphous Raltegravir potassium (250 mg)and placed in a closed 100 mL vessel containing cyclopentyl methyl ether(20 mL) at room temperature. The vessel was kept at room temperature for40 days. The product was dried overnight in a vacuum oven at 45° C. toobtain Raltegravir potassium Form IXb.

Example 17 Preparation of Raltegravir Potassium Form X

A vial (20 ml) was charged with Raltegravir free hydroxy (0.5 g) andacetonitrile (7.5 mL) to obtain a solution. KOH 85% (75.6 mg) was addedto the solution at room temperature. The solution was then sonicated for40 minutes. The product was isolated by vacuum filtration to provideRaltegravir potassium Form X.

Example 18 Preparation of Raltegravir Potassium Form XI

Raltegravir potassium crystalline Form X, prepared according to example17, was dried overnight in a vacuum oven at 45° C. to provideRaltegravir potassium crystalline Form XI.

Example 19 Preparation of Raltegravir Potassium Form XII

A 50 ml flask with magnetic stirrer was charged with Raltegravir freehydroxy (3 g, 99.66% purity, 90.73 assay). Acetonitrile (26.2 ml, 8.62vol) was added to form a slurry. The slurry was heated to 45° C. till aclear solution was obtained. Hot filtration was done and the filteredsolution was reheated to 45° C., KOH 30% solution was added dropwise (1ml, 0.99 eq) during 15 minute (after addition of the KOH solution,precipitation was observed). The solution was cooled over 4 hour to RT,forming a slurry. The slurry was filtered and the collected product waswashed with acetonitrile (1 ml). The product was dried under vacuum at40° C. overnight to obtain Raltegravir potassium crystalline Form XII(2.7 g, 99.63% purity).

Example 20 Preparation of Raltegravir Potassium Form XIII

A vial (20 ml) was charged with Raltegravir free hydroxy (0.25 g) andpentanol (2 mL) to form a solution. KOH 85% (38 mg) was added at roomtemperature, forming a solution. This solution was stirred for 3 hours.The product precipitated and was isolated by centrifuge filtration. Theisolated product was dried in a vacuum oven at 40° C. for 5 h to obtainRaltegravir potassium crystalline Form XIII.

Example 21 Preparation of Raltegravir Potassium Form XIV

A vial (20 ml) equipped with a magnetic stirrer was charged withRaltegravir free (250 mg) and toluene (2.5 mL). A clear solution wasobtained. KOH 30% (80 μL) was added at room temperature and the reactionwas stirred for five hours. A solid precipitate formed and was separatedby filtration. The product was dried in a vacuum oven at 45° C. forovernight to obtain Raltegravir potassium Form XIV.

Example 22 Preparation of Raltegravir Potassium Form XV

A vial (20 ml) was charged with Raltegravir free (0.25 g) and pentanol(2 mL), forming a solution. KOH 85% (38 mg) was added at roomtemperature. The solution was stirred for 3 hours. The productprecipitated and was isolated by centrifuge filtration. The wet samplewas analyzed showed that Raltegravir potassium crystalline Form XV wasobtained.

Example 23 Preparation of Raltegravir Potassium Form XV

Raltegravir free hydroxy (40 mg) was suspended in 2 mL of isopropanol,and KOH-1 g/mL (100 micro L) was added. The mixture was left on a shakerfor 3 hours. Wet crystals were isolated and analyzed showing thatRaltegravir potassium Form XV was obtained.

Example 24 Preparation of Raltegravir Potassium Form XVI

A 100 mL flask equipped with mechanical stirrer was charged with water(1 vol), KOH 85% (1 eq) and Raltegravir free Form A1 (5 g), and a clearsolution was obtained. The solution was cooled in an ice bath. Toluene(9 vol) was added, and seeds of Raltegravir potassium Form V were added,forming a slurry. The slurry was stirred overnight and filtered to givea wet sample of Form XVI.

Example 25 Preparation of Raltegravir Sodium Form S1

A vial (20 ml) was charged with Raltegravir free hydroxy (250 mg) andacetone (6 ml). A solution of NaOH-1N (0.56 ml) was added. The resultingsolution was stirred for 24 h at room temperature and then for 16 h at4° C. Diethylether (10 ml) was added and the resulting mixture wasstirred for an additional 16 h at 4° C. A solid precipitated and wasfiltered under reduced pressure and dried overnight in a vacuum oven at45° C. The resulting product was analyzed by XRPD which showed a patternof Raltegravir sodium crystalline Form S1.

Example 26 Preparation of Raltegravir Sodium Form S2

A vial (20 ml) was charged with Raltegravir free hydroxy (250 mg) andcyclohexane (5 ml). A solution of NaOH-1N (0.56 ml) was added. Theresulting solution was stirred for 24 h at room temperature and a solidprecipitated. The solid was filtered under reduced pressure and driedovernight in a vacuum oven at 45° C. The resulting product was analyzedby XRPD which showed a pattern of Raltegravir sodium crystalline FormS2.

Example 27 Preparation of Raltegravir Sodium Form S2

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g) and acetone (50 ml). A solution of NaOH-1N (11.2 ml)was added, to obtain a suspension. Heating to 40° C. led to dissolution.The solution was then cooled to room temperature and stirred.Precipitation did not occur at this point. Diethyl ether (20 ml) wasadded and the solution was stirred overnight during which time a solidprecipitated. The solid was filtered under reduced pressure and driedovernight in a vacuum oven at 55° C. The resulting product was analyzedby XRPD which provided a pattern of Raltegravir sodium crystalline FormS2.

Example 28 Preparation of Raltegravir Sodium Form S2

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g) and acetonitrile (50 ml). A solution of NaOH-1N (11.2ml) was added to obtain a suspension. Heating to 40° C. led todissolution. The solution was cooled to room temperature and stirred.Precipitation did not occur at this point. Diethyl ether (20 ml) wasadded and the solution was stirred overnight during which time a solidwas precipitated. The solid was filtered under reduced pressure anddried overnight in a vacuum oven at 55° C. The resulting product wasanalyzed by XRPD to give a pattern of Raltegravir sodium crystallineForm S2.

Example 29 Preparation of Raltegravir Sodium Form S2

A three necked round bottom flask was charged with Raltegravir freehydroxy (5 g) and ethyl acetate (50 ml). A solution of NaOH-1N (11.2 ml)was added to obtain a suspension. Heating to 40° C. led to dissolution.The solution was cooled to room temperature and stirred. Precipitationoccurred and the solid was filtered after 4 hours under reduced pressureand dried overnight in a vacuum oven at 55° C. The resulting product wasanalyzed by XRPD which provided a pattern of Raltegravir sodiumcrystalline Form S2.

Example 30 Preparation of Raltegravir Sodium Form S3

A vial (20 ml) was charged with Raltegravir free hydroxy (250 mg) andmethyl-formate (7.5 ml). A solution of NaOH-1N (0.56 ml) was added. Theresulting solution was stirred for 24 h at room temperature and then for16 h at 4° C. Diethylether (7.5 ml) was added and a solid wasprecipitated. The solid was filtered under reduced pressure and driedovernight in a vacuum oven at 45° C. The resulting product was analyzedby XRPD which provided a pattern of Raltegravir sodium crystalline FormS3.

Example 31 Preparation of Raltegravir Lithium Salt

Raltegravir free hydroxy (25.2 mg) was suspended in acetone (0.250 mL),and 1M aqueous lithium hydroxide solution (0.062 mL) was added in oneportion. The mixture was shaken well and a clear solution was obtainedwithin a few seconds. The solvent was allowed to evaporate under a flowof nitrogen and the resulting solid residue was dried at ambienttemperature under vacuum for approximately 24 hours. The product wascharacterized by XRPD.

Example 32 Preparation of Raltegravir Calcium Salt

A physical mixture of Raltegravir free hydroxy (25.8 mg) and calciumhydroxide (˜4.6 mg) was suspended in 70/30 tetrahydrofuran/water. Themixture was shaken well and the resulting suspension was temperaturecycled between room temperature and 50° C. using a Heidolph shaker andincubator with a power source programmed to switch on and off every 4hours. After approximately 72 hours, excess solvent was decanted offusing a syringe and the solid residue was dried at ambient temperatureunder vacuum for approximately 24 hours. The product was characterisedby XRPD.

Example 33 Preparation of Raltegravir t-Butylamine Salt

Raltegravir free hydroxy (24.6 mg) was suspended in ethyl acetate (0.250mL) and tert-butylamine (6.5 μl) was added. The mixture was shaken welland the resulting suspension was temperature cycled between ambient and50° C. using a Heidolph shaker and incubator with a power sourceprogrammed to switch on and off every 4 hours. After approximately 72hours excess solvent was decanted off using a syringe and the solidresidue was dried at ambient temperature under vacuum for approximately24 hours. The product was characterised by XRPD.

Example 34 Preparation of Raltegravir Tert-Butylamine Salt

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g), iso-propyl alcohol (45 ml) and water (5 ml) toobtain a mixture. The mixture was heated to 40° C. and tert-butylamine(1300 μl) was added drop-wise. There was almost dissolution and heavyprecipitation subsequently occurred. The obtained solid was filteredunder reduced pressure and dried overnight in a vacuum oven at 55° C.The resulting product was characterised by XRPD.

Example 35 Preparation of Raltegravir Tert-Butylamine Salt

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g), ethanol (45 ml) and water (5 ml) to obtain amixture. The mixture was heated to 40° C. and tert-butylamine (1300 μl)was added dropwise. There was almost dissolution and heavy precipitationsubsequently occurred. The precipitate was filtered under reducedpressure and dried overnight in a vacuum oven at 55° C. The resultingproduct was characterised by XRPD.

Example 36 Preparation of Raltegravir Tert-Butylamine Salt

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g) and acetone (50 ml) to obtain a mixture. The mixturewas heated to 40° C. and tert-butylamine (1300 μl) was added dropwise.There was dissolution and heavy precipitation subsequently occurred. Theprecipitate was filtered under reduced pressure and dried overnight in avacuum oven at 55° C. The resulting product was characterised by XRPD.

Example 37 Preparation of Raltegravir Tert-Butylamine Salt

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g) and ethyl acetate (50 ml) to obtain a mixture. Theobtained mixture was heated to 40° C. and tert-butylamine (1300 μl) wasadded drop-wise. There was dissolution and heavy precipitationsubsequently occurred. The precipitate was filtered under reducedpressure and dried overnight in a vacuum oven at 55° C. The resultingproduct was characterised by XRPD.

Example 38 Preparation of Raltegravir Tert-Butylamine Salt

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g), ethanol (65 ml) and water (10 ml) to obtain amixture. The obtained mixture was heated to 40° C. and a solution oftert-butylamine (1300 μl) in ethanol (2 ml) was added dropwise. Afterdissolution, the solution was cooled to room temperature. Precipitationoccurred and the obtained solid was filtered under reduced pressure anddried overnight in a vacuum oven at 55° C. The resulting product wascharacterised by XRPD.

Example 39 Preparation of Raltegravir Tert-Butylamine Salt

A three necked round bottom flask (100 ml) was charged with Raltegravirfree hydroxy (5 g) and acetone (75 mL) to obtain a mixture. The obtainedmixture was stirred and dissolved at room temperature. tert-Butylamine(1300 μl) in acetone (2 ml) was added dropwise. Heavy precipitationoccurred and the obtained solid was filtered under reduced pressure anddried overnight in a vacuum oven at 55° C. The resulting product wascharacterised by XRPD.

Example 40 Preparation of Raltegravir Diethylamine Salt

Raltegravir free hydroxy (24.6 mg) was suspended in ethyl acetate (0.250mL) and diethylamine (6.4 μl) was added. The mixture was shaken well andthe solid dissolved on heating. The resulting solution was temperaturecycled between ambient and 50° C. using a Heidolph shaker and incubatorwith a power source programmed to switch on and off every 4 hours. Afterapproximately 72 hours the solvent was allowed to evaporate under a flowof nitrogen and the solid residue was dried at ambient temperature undervacuum for approximately 24 hours. The product was characterised byXRPD.

Example 41 Preparation of Raltegravir Diisopropylamine Salt

Raltegravir free hydroxy (25.2 mg) was suspended in toluene (0.250 mL),and diisopropylamine (8.7 μl) was added to the suspension. The mixturewas shaken and the resulting suspension was temperature cycled betweenambient and 50° C. using a Heidolph shaker and incubator with a powersource programmed to switch on and off every 4 hours. Afterapproximately 72 hours, excess solvent was decanted off using a syringeand the solid residue was dried at ambient temperature under vacuum forapproximately 24 hours. The product was characterised by XRPD.

Example 42 Preparation of Raltegravir Free Hydroxy Form A1

A solution of Raltegravir potassium (−3.4 g) in water was acidified with2N HCl until pH 2 was obtained. The acidified solution was extractedwith mixture of methyl tert-butyl ether (MTBE)/isopropyl alcohol (IPA)(400 ml/100 ml). The organic extract was evaporated to dryness.Raltegravir free hydroxy (3.1 g) was obtained as a white powder.

Example 43 Preparation of Raltegravir Free Hydroxy Form A1

A solution of Raltegravir potassium (˜2 g) in water was acidified with2N HCl until pH 2 was obtained. The acidified solution was extractedwith MTBE (600 ml). The organic extract was evaporated to dryness.Raltegravir free hydroxy (1.5 g) was obtained as a white powder.

Example 44 Preparation of Raltegravir Free Hydroxy Form A2

A vial (20 ml) was charged with Raltegravir free hydroxy form A1 (500mg) and cyclohexane (2.5 ml). The mixture was heated to 50° C. and thencooled to room temperature. Distilled water (0.159 ml) was added to thecooled mixture. The resulting mixture was stirred for 24 h at roomtemperature. A solid precipitated and was separated by filtration underreduced pressure to obtain Raltegravir free hydroxy crystalline Form A2.The resulting product was analyzed by XRPD to be Raltegravir freehydroxy Form A2.

Example 45 Preparation of Raltegravir Free Hydroxy Form A3

A 2 L flask with magnetic stirrer was charged with Raltegravir freehydroxy (23 g/26 g). Methanol (1600 ml, 32 vol was added and theresulting slurry was heated to reflux. A clear solution was therebyobtained. The solution was cooled slowly to RT over 8 hours to form aslurry. The slurry was filtered and the collected product was washedwith methanol (20 ml). The product was then dried under vacuum at 40° C.overnight to obtain Raltegravir free hydroxy Form A3.

Example 46 Preparation of Raltegravir Potassium Form V

A 100 ml three necked round bottom flask equipped with mechanicalstirrer was charged with Raltegravir free-hydroxy (2 g) and THF (15vol., 30 mL), and a clear pinkish solution was obtained. A solution ofKOH 87.7% (277 mg, 1.05 equiv.) in H₂O (2 vol.) was added dropwise. Theresulting clear yellow solution was cooled to 0° C. in ice bath. Seedsof Raltegravir potassium form V were added, forming a slurry. The slurrywas stirred for 2.5 hours, filtered at 0° C. and the separated solid waswashed with cold THF (6 ml). The obtained product was dried in a vacuumoven at 40° C. overnight to obtain Raltegravir potassium crystallineform V.

Example 47 Preparation of Raltegravir Potassium Form V

A 250 ml three necked round bottom flask equipped with mechanicalstirrer was charged with Raltegravir free-hydroxy (2 g) and THF (15vol., 30 ml), and a clear pinkish solution was obtained. A solution ofKOH 87.7% (277 mg, 1.05 equiv.) in H₂O (2 vol.) was added dropwise. Theresulting clear yellow solution was cooled to 0° C. in ice bath. Seedsof Raltegravir potassium form V were added, forming a slurry. The slurrywas stirred for 2.5 hours and filtered at 0° C. and washed with cold THF(6 ml). The product was dried in a lyophilizer to produce Raltegravirpotassium crystalline form V.

Example 48 Preparation of Raltegravir Meglumine Salt

A three necked round bottom flask (50 ml) was charged with Raltegravirfree hydroxy (300 mg), Meglumine (132 mg), THF (15 mL) and water (7.5mL) to obtain a mixture. The mixture was stirred at room temperature,yellow clear solution was obtained. The solution was evaporated anddried overnight in a vacuum oven at 60° C. The resulting product wascharacterised by XRPD.

What is claimed is:
 1. Crystalline Raltegravir sodium.
 2. The crystalline form of Raltegravir sodium according to claim 1, selected from the group consisting of: a) Form S1, characterized by: an X-ray powder diffraction pattern having peaks at 7.9, 11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 12; and combinations thereof; b) Form S2, characterized by: an X-ray powder diffraction pattern having peaks at 7.8, 11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 13; a solid-state ¹³C NMR spectrum with signals at 134.3, 146.1, 149.0, 153.9 and 170.5±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 124.3, 136.1, 139.0, 143.9 and 160.5±0.1 ppm; a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 33; and combinations thereof; and c) Form S3, characterized by: an X-ray powder diffraction pattern having peaks at 8.1, 13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 14; and combinations thereof.
 3. The crystalline Form S1 of Raltegravir sodium according to claim 2, characterized by: an X-ray powder diffraction pattern having peaks at 7.9, 11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 12; and combinations thereof.
 4. The crystalline Form S1 of Raltegravir sodium according to claim 3, characterized by an X-ray powder diffraction pattern having peaks at 7.9, 11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta, and further characterized by an X-ray powder diffraction pattern having additional peaks at 14.0, 15.0, 23.9 and 27.8 degrees two theta±0.2 degrees two theta.
 5. The crystalline Form S2 of Raltegravir sodium according to claim 2, characterized by: an X-ray powder diffraction pattern having peaks at 7.8, 11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 13; a solid-state ¹³C NMR spectrum with signals at 134.3, 146.1, 149.0, 153.9 and 170.5±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 124.3, 136.1, 139.0, 143.9 and 160.5±0.1 ppm; a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 33; and combinations thereof.
 6. The crystalline Form S2 of Raltegravir sodium according to claim 5, characterized by an X-ray powder diffraction pattern having peaks at 7.8, 11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta.
 7. The crystalline Form S2 of Raltegravir sodium according to claim 6, further characterized by X-ray powder diffraction pattern having additional peaks at 14.6, 17.2, 23.6, 28.1 and 29.1 degrees two theta±0.2 degrees two theta.
 8. The crystalline Form S3 of Raltegravir sodium according to claim 1, characterized by: an X-ray powder diffraction pattern having peaks at 8.1, 13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 14; and combinations thereof.
 9. The crystalline Form S3 of Raltegravir sodium according to claim 8, characterized by: an X-ray powder diffraction pattern having peaks at 8.1, 13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta.
 10. The crystalline Form S3 of Raltegravir sodium according to claim 9, further characterized by X-ray powder diffraction pattern having additional peaks at 20.3, 23.1, 27.4, 30.2 and 32.5 degrees two theta±0.2 degrees two theta.
 11. Raltegravir calcium salt.
 12. Raltegravir calcium salt according to claim 11 in crystalline form.
 13. The crystalline Raltegravir calcium salt according to claim 12, characterized by: an X-ray powder diffraction pattern with peaks at 6.5, 9.9, 18.0, 19.0 and 21.1 degrees two theta 0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 16; and combinations thereof.
 14. Raltegravir tert-butyl amine salt.
 15. The Raltegravir tert-butyl amine salt according to claim 14 in crystalline form.
 16. The crystalline Raltegravir tert-butyl amine salt according to claim 15, characterized by: an X-ray powder diffraction pattern with peaks at 12.4, 16.7, 17.9, 18.6 and 20.9 degrees two theta 0.2 degrees two theta; an X-ray powder diffraction pattern with peaks at 4.2, 6.6, 8.4, 16.9 and 21.1 degrees two theta 0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in FIG. 17 or FIG. 26; a solid-state ¹³C NMR spectrum with signals at 121.7, 130.2, 141.6, 152.0±0.2 ppm; a solid-state ¹³C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 110.4, 118.9, 130.3 and 140.7±0.1 ppm; a solid-state ¹³C NMR spectrum substantially as depicted in FIG. 34; and combinations thereof.
 17. The crystalline Raltegravir tert-butyl amine salt according to claim 16, further characterized by X-ray powder diffraction pattern having additional peaks at 9.2, 10.2, 12.6, 13.8, 15.2 and 18.0 degrees two theta±0.2 degrees two theta.
 18. A pharmaceutical composition comprising the Raltegravir salt according to any one of claims 1, 11, or 14 and at least one pharmaceutically acceptable excipient.
 19. A method of treating a patient with HIV, comprising administering to said patient an effective amount of the pharmaceutical composition according to claim
 18. 20. A process for preparing Raltegravir potassium comprising reacting at least one Raltegravir salt according to any one of claims 1, 11, or 14 with a potassium base.
 21. The process of claim 20, wherein said process comprises converting the at least one Raltegravir salt to Raltegravir free hydroxy prior to reacting with a potassium base.
 22. The process of claim 21, wherein the at least one Raltegravir salt is in solid state when converted to Raltegravir free hydroxy prior to reacting with a potassium base. 